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Charles Ryan: Hello, I'm delighted today to be joining Clayton Yates PhD. He's the John Lewis Endowed Chair of Pathology at Johns Hopkins University, where he directs the health disparities and Global Health Equity program, and he's the principal investigator of a challenge award that's entitled MET-PAAM, which is an acronym. This is Elucidating the Molecular Mechanisms of Tumor Progression in Metastatic Prostate Cancer Among Men of African Ancestry. It's a really important topic, and one we're learning a lot about through this Health Equity Challenge award. Dr. Yates, thank you so much for joining me today, and I'm excited to hear about your work.

Clayton Yates: Thank you for having me and inviting us.

Charles Ryan: So tell us a little bit about the background of this work, and how it got started, and the direction you're taking.

Clayton Yates: Yeah, absolutely. So for many years, my lab has been focused on disparities, or looking at the biological contribution, or the tumor biology associated with why diseases so aggressive, particularly in African American men. And as the years progressed, we've gone from low tech, I'm going to say, low tech biomarker discovery. Some of the first discoveries in our lab were some micro rays and doing lots of history, chemistry, just looking at size slides, to now, we're in really high tech, high throughput areas, where we could start to look and screen more deeply and more carefully and more, I guess also, with a more precision approach. Understanding some of the molecular features that are driving particularly, folks in the aggressive disease that we know African American men have a worse outcome. So our work has been focused on, not to discount any of the social factors access to health, but we do see a biological contribution to the disease and its aggressiveness.

And so over the years, it's just evolved. And then collaboration with Franklin Huang as well as Elisabeth Heath. We've all been in this space together, and we decided to come together to do something that I think is really important. A lot of work has been done in primary tumors. It's precluding some from individually amongst my co-PIs as well as myself. It's really hard to understand the contributions of metastatic disease, because of just the way metastasis progresses in a patient that's normally not really accessible for research, it's just because those folks, they're sort of at the end of the continuum of care. And so we came together, pulled out resources from institutions, as well as our collective knowledge, to come in to really ask this question, what is going on in driving particularly metastatic disease or aggressive hormone insensitive and sensitive metastatic disease in African American men?

Charles Ryan: So in the population in general, let's just say, we know there are many biological differences between what you look at in the population of primary tumors versus metastatic tumors. We also are beginning to see, as your team is helping us find out, that when we look at primary tumors of African Americans versus non-African Americans, there's sometimes biological differences detected. So you're saying, there's even a fourth quadrant, if you will, which is metastasis versus primaries in black men versus white men?.

Clayton Yates: Yeah, we believe so. We had some sort of early evidence, some genes that were identified in primary tumors, particularly high MEK expression. We just published a paper in Nigerian men that there were BRCA variants that seemed to be different or quasi driving tumor aggressive in African American men. We think those carry over and actually accumulate in metastatic disease.

Charles Ryan: And so, tell us a little bit about the population that you've studied. You've indicated both Nigerian men as a population you've studied and African American men. Tell us how those populations are perhaps different, or how your work may be looking at those differently?

Clayton Yates: Well, so it came apparent to us in our disparity work that, I think one major sort of factor to quantify this is that as again, as we progressed over the years, we felt as a field, it wasn't sufficient just to say there was a difference by race. Because race means different things to different people. And so the field, including my lab as a whole, started to understand the contribution of genetic ancestry. And we thought that also provided rigor to the field, because if we could quantify the contribution of a sickle gene and link it to a genetic ancestral trait, then that also had to, could be a driver of the disease. So as the field of ancestral, particularly in African Americans, and we know many African Americans, and just Americans in general, is a melting pot or admix, if we really wanted to understand the contribution of genetic ancestry, or what it meant of African ancestry, we needed to study Africans.

And so, for logically, for me, it was a progression of a logical chain of thoughts, that we needed a population that didn't have the admixture that we see in African American men, that we could understand some of those. If it were true that there were genetic drivers, then they should be present in ancestral less, admixed population, such as Native Africans. And so, we started to study people from Nigeria or West Africa. I actually co-direct the Prostate Cancer Transatlantic Consortium with Folakemi Odedina, and we have been doing this work for many years. And we just decided that we would only take this genome sequencing as one of many projects within the consortium.

Charles Ryan: So Africa itself obviously, is incredibly diverse, and you've chosen Nigeria as sort of the model for a West African population. Do African Americans, as we commonly refer to this group, resemble genetically West Africans in their descent, in terms of cancer risk and things like that?

Clayton Yates: So predominantly, and again, there's definitely variation across the population, but large percent of African Americans share West African ancestry. If you think about the transatlantic slave trade that's over the coast there, that's where the slave ports were within West Africa, down that western coast, Ghana, Nigeria, so on. So a large percent of African Americans here share West African ancestry. So we thought it was appropriate.

Charles Ryan: Okay. So let's talk a little bit about the translational aspects of this. What is the driving hypothesis, or the vision, if you will, of your work, and how it may help us to understand how we may treat or personalize therapies, or understandings of the disease moving forward?

Clayton Yates: So I'll take it sort of twofold. One, we just published this paper on identifying the whole genome sequencing in Nigerian men. What we found there was that, there were African American, as well as African ancestry specific BRCA variants, that are not being tested in our current molecular profiling panel. We also show that these variants were associated with worse outcomes, and particularly in African Americans.

And so again, adding to, we know the significance of BRCA gene, we know the significance, BRCA1, BRCA2, as far as candidates for certain types of therapy, such as PARP inhibitors. Or even now as far as immunotherapy, as you spoke with my graduate student, Israel, who's focused on the SPOP mutations. And so, we start to understand how these sort of molecular tests guide therapy, is really important to have the guided therapy representative of the population as well in those molecular profiling tests. So our goal is to add to the plethora of panels of variants, particularly not just genes, but also African ancestry specific variants, so that we understand the population as a whole.

Charles Ryan: Yeah.

Clayton Yates: I think that is a approach we're taking. It's a precision under the precision medicine umbrella. And we feel that adds to the overall, hopefully, better outcome for individuals with have to suffer from cancer.

Charles Ryan: So for example, with BRCA2 mutations, as you've alluded to, we commonly think of a founder BRCA2 mutation may have occurred in, let's say for example, an Ashkenazi Jewish population.

Clayton Yates: Yep.

Charles Ryan: Because we see that association. But an African, a patient of African descent, with a BRCA2 mutation, may have an entirely different mutation in BRCA2, and may therefore have an entirely different experience, when treated with a PARP inhibitor, for example.

Clayton Yates: And so that's what we showed. We showed this at a different BRCA2, and that has not been tested, so that's what we have done. And again, the Ashkenazi Jewish panel population, panel of BRCA2 BRCA variants, is what's being clinically tested, not from another population. Matter of fact, any other population. And so, we feel this is critical, not just for African Americans, but a population as a whole, to start to understand these differences, and then add those. And understand what their impact is in as far as PARP inhibitors or other types of therapies.

Charles Ryan: Right. So Clayton, in an unselected population, we see that BRCA mutations are maybe comprised eight to 10% of prostate cancer cases. Is it about the same number in the population you studied of Nigerian men? And do they have the same risk of other cancers that are commonly associated with BRCA?

Clayton Yates: No. So we also, what we saw was that, in our BRCA mutation there, especially the germline, it was in 100% of individuals. We also have, not to spill the stories that another follow up manuscript being developed that, if you look across even a larger cohort, it sort of pans out to around 92%. Okay. And then if you profile that BRCA variant in African American men, it was to right around 68%. And I think, one of the real interesting sort of aspects of our story is that, when we utilize our ancestry as ancestry informative markers, as sort of understanding of the correlation of these variants based on ancestry, if you start to look at the percent ancestry, so you can take a person who's 90%, 80%, 70%, 60, 30, and you sort of swing that to also a European individual who's 100%, and sort of go the other way. What happens is you can see the variant titrate out.

Charles Ryan: Interesting.

Clayton Yates: Right. So you can see the variant titrate down as a person, particularly even in African American who has more admixture, there's a less incidence or frequency of that variant. And then there's also almost completely absent in almost 100% European ancestry individuals. So again, we feel like this is why it was some of the key findings and importance of this work.

Charles Ryan: And then the other cancers with regards to pancreas, breasts, and other cancers that are seen with BRCA?

Clayton Yates: So we don't know much about pancreas, but we do see certain BRCA variants Olufunmilayo Olopade's work, particularly in the Nigerian population as well, shown very similar BRCA variances is which we have, and also with the same penetrance. Also we see in, I'm not sure as BRCA, but definitely APC, which we showed also as important in colorectal tumors as well.

Charles Ryan: Excellent. And your work, and I spoke with your graduate student, Dr. L, or I guess not Dr, I guess she is a Dr. L, You could say.

Clayton Yates: Yeah, she's a physician.

Charles Ryan: She is, last week. And there was a strong evident sign of inflammatory markers within the data that she was looking at with the patient she was analyzing, and there were implications perhaps for immunotherapy. Do you have a sense, in terms of that observation around inflammatory markers, does that help us look into how there might be a different causative or environmental risk for prostate cancer in people of African descent? Or is that entirely separate from causation?

Clayton Yates: Well, so to the answer, the short answer to the question is, we not quite know yet. But what we do know is that, not just our work, but it's been replicated many times, that African American men have a chronic low level inflammatory type disease. And these are drivers.

What Israel's work showed was that, these patients simultaneously have an SPOP mutation, and that the patients who don't have this don't have this inflammatory type signature. So if you start to think about this inflamed or chronic inflammation, that's going to attract an immune response that we also think is coinciding with a possible response to immunotherapy. And this is really important because as a whole, prostate cancers have been typically what we characterize as cold tumors. When I mean cold is that, there's no inflammation, there's no immune response, there's not a lot of immune cells. And traditionally in clinical trials, prostate tumors have not done well because of that, the lack of actual immune cells. And so these immunotherapies, which are just changing lives and so promising, have sort of evaded prostate cancer, just because that the lack of immune cells, what we feel like by subtyping, and defining ancestry, and understanding the causation, whether it's genetic and/or epigenetic of these inflammatories type and characterizing, we might can subtype prostate cancer, and there could be a population of patients that could benefit from immune therapy.

Charles Ryan: So do you think it's chronic inflammation on the backdrop of an SPOP mutation that leads to carcinogenesis in these individuals? Or is it inflammation that leads to the outgrowth of an SPOP mutated group of cells? In other words, I think I'm asking you an impossible question, but it's sort a which comes first, the SPOP mutation or the inflammation?

Clayton Yates: So what I can tell you in our study, what we didn't find was a germline SPOP.

Charles Ryan: Yeah.

Clayton Yates: So there's also a paper that we actually did an opinion piece in Trends in Cancer. It'll be out, it was accepted that this week, and it'll be out from the Vanessa Hayes group and who was out of Australia, who just profiled, I think 183 African sub-African prostate cancer patients. And their data confirmed our SPOP mutations, data that we showed, which was actually very encouraging, just showed that this is actually real, even in a larger cohort.

But it also, they didn't see a germline SPOP, and we didn't see any germline SPOP. We saw germline BRCA variants, BRCA1, BRCA2 variants, but we didn't see any germline. So there very could be a causational inflammatory that's predisposing SPOP mutations, or it could be environmental as well. These are studies that we still have to start to understand. Is it the environment that predisposes chronic inflammation predisposes to subsequent mutations that are driving and keep them up, that are sort of driving the disease. But what we did find is that, even in African Americans who did not have the SPOP mutation, they didn't have the inflammatory response. They had a different, so there was an immune type signature, but it was not the same. It was more of even a low level that the heightened immune response that all the other manuscripts, there's so many other manuscripts that have shown African Americans have, that was not present in the SPOP wild type, they were non-mutant patients.

Charles Ryan: I see. And if I recall correctly, the SPOP mutation is seen in about 20% of the African population. So it's not an inconsequential mutation.

Clayton Yates: It's not inconsequential. Yes. That's correct.

Charles Ryan: Yeah. So looking forward, what you're getting at here I think is, really one of these areas where we could see kind of environment and genetics coming together to mediate risk in this population, when you think about a mutation and you think about inflammation. And one of the great challenges we have in this country is clinical trial enrollment, and identifying subpopulations who do or do not benefit from particular therapies. What would you say are the key things that we can communicate to African American patients in this country with prostate cancer around the diversity of the disease, even within that population, how that might be integrated into an approach for seeking to improve outcome through clinical trial enrollment?

Clayton Yates: As a basic, I like to call myself as a basic sort of translational scientist. Diversity in clinical trials is important. We have to understand how certain therapies, therapeutic interventions, affect multiple populations. But I also think making a biological case, prior to in the design of the clinical trials, equally important to recruiting minority populations into clinical trials.

So for example, we all know the research continuum. You do your research, you run all your models, and then you say, "Hey, I want to start a clinical trial." And then we think about diversity. Well, from our work, we're thinking about diversity at the designs of the biology that's predisposing a certain population that we want to test in a clinical setting. And so again, we feel, I feel, and I think there's some evidence to this as well, is that, that makes a stronger case. If you're going to a population, particularly that's been marginalized, for the time that we did the research, we understood this is prevalent in population, we can show you the data, and this is why you would benefit from this clinical trial contribution. We feel like that's a stronger case for enrollment and diversity across the whole clinical trial spectrum.

Charles Ryan: Right. And you can only imagine the implications of demonstrating, for example, that a certain PARP inhibitor may have greater efficacy or lesser efficacy in an African descent population, based on the uniqueness of that mutation, relative to the mutation that we see in other populations.

Clayton Yates: Absolutely.

Charles Ryan: Well, congratulations on this award. It's fascinating work, and I really want to make sure we're able to communicate the results and educate the clinician population, as well as the patient population, around this work, because it is shaping how we think of this disease, certainly shaping how we conduct clinical research in this disease. So in the final moments here, give us a sense of your vision of the next steps for you and your team.

Clayton Yates: The next step for us is really to understand how to translate this. Right? So to translate our findings., We're really focused on understanding the key factors and I guess what I want to say, they're the puzzle. And then, so as putting all the pieces of the puzzle together that can ultimately benefit and improve health outcomes, as you mentioned, understanding what does that mean from a biological perspective, and then being able to understand what does that mean in a clinical setting to patients every day who are suffering from the disease is really our key goal. And so adding pieces to the puzzle, with the sensitivity of understanding the vulnerabilities of our population, is where we're focus every day, and we hopefully want to improve health outcomes at the end of the day.

Charles Ryan: Well congratulations to you and your team for the receipt of a Pfizer Health Equity Global Challenge Award from the Prostate Cancer Foundation. We're delighted to be sponsoring this work, and look forward to your results.

Clayton Yates: Thank you very much for having me.